The present invention relates to tricyclic compounds of the 11-oxo-dibenzodiazepin and dibenzoazepin families, and their new therapeutic uses as defibrillating, and/or anti-fibrillatory, and/or anti-arrhythmic and/or anti-ischemic drugs. More particularly, the present invention relates to 5(N-acyl)-derivatives and 5(N-β-aminoalcohol)-derivatives of 11-oxo-10,11-dihydro-dibenzo[b,e] [1,4]diazepin and 10,11-dihydro-dibenzo[b,f]azepin, compositions including same, methods of their synthesis, purification and formulation and their use in prevention and treatment of cardiac disorders, such as, but not limited to, arrhythmia and ventricular fibrillation.
Sudden cardiac death is a leading cause of mortality, and ventricular fibrillation (VF) is thought to play a major role in sudden cardiac death [1]. Ventricular fibrillation can be divided into two categories: sustained VF (SVF), which is fatal, unless external defibrillating intervention is practiced, or transient VF (TVF), which terminates spontaneously. Currently, only one effective approach has been found to terminate SVF once SVF is initiated, which is the application of electrical defibrillation. Electrical defibrillation can be applied either externally or internally, by implantation. However, this approach has a number of disadvantages. For example, electrical defibrillation must be applied immediately to be effective, yet may not be sufficient, and may even cause damage. In addition, an implanted defibrillator requires invasive treatment. Thus, artificial defibrillation is not a cure, and does not prevent reoccurrence of VF.
Antiarrhythmic drugs constitute an alternative, preferable approach, as they are aimed at preventing initiation of VF by decreasing the incidence of ventricular arrhythmias that can lead to VF [2]. In addition, certain drugs, such as bretylium, have been shown to transform SVF into TVF [3]. The effectiveness of this treatment, however, is limited, since various mechanisms can be involved in the initiation of VF, such that antiarrhythmic drugs are unlikely to absolutely eliminate arrhythmias and totally prevent VF initiation. Furthermore, recent surveys (such as the Cardiac Arrhythmia Suppression Trial, CAST, II and I [4,5], have clearly shown limitations to this approach. Thus, a new cardiac protective therapy is needed. For this reason, a new approach has been proposed, to use a new class of antiarrhythmic drugs [6], which can enhance spontaneous termination of VF, once it occurs. In several animal species, and even, though rarely, in humans, VF can revert spontaneously into sinus rhythm, resulting in the non-fatal TVF. It has been previously found that several factors contribute to the ability to self-defibrillate. For example, self-defibrillation is a normal feature of young mammals, but this ability decreases with age [7]. Such spontaneous defibrillation requires a relatively high degree of intercellular synchronization [8], and is enhanced by increased sympathetic activity. Thus, treatments with compounds that elevate extraneuronal catecholamine levels in the heart enhance self-defibrillation and administration of β-adrenergic blockers abolishes this activity [9].
In order to design and synthesize new, more potent and selective defibrillatory drugs, it has been found that certain dibenzoazepins (imipramine, desipramine, maprotiline and bonnecore) and phenothiazins (chlopromazin, moricizine and trifluoperazin), induce self-defibrillation and increase the threshold for electrical fibrillation [10, 11]. Moreover, tricyclic antidepressants, in addition to their antiarrhythmic and defibrillating effects, have the ability to decrease the ischemic area in the heart following coronary occlusion [12]. However, these cardio-protective effects of the compounds were expressed when relatively high doses were used, resulting in a low therapeutic index.
There is thus a need for, and it would be useful to have, pharmaceutically effective compounds which are safe and useful for the treatment of ventricular fibrillation, particularly for the induction of TVF once SVF has been initiated, and for both treating and preventing pathological conditions associated with VF.